Nervous system disease is one of prevalent diseases in contemporary society. However, many types of nervous system diseases have not yet been effectively addressed in clinical practice. In particular, the treatments for neurological diseases such as schizophrenia, Parkinson's disease and the like are still very far from achieving satisfactory results. In recent years, studies have shown that schizophrenia is considered as the result of D1 receptor dysfunction of medial prefrontal cortex (mPFC) and thus enhancing the activity of D2 receptor of the ventral tegmental area (VTA) and the nucleus accumbens region (NAc). By carrying out working memory experiments for animals and patients, short-term experiments reflecting the function of medial prefrontal cortex and clinical trials, scientists have demonstrated that the inactivation of D1 receptor is related to the negative symptoms of schizophrenia and high activity of D2 receptor generates the positive symptoms. Based on such hypothesis, if a class of medicaments can effectively excite the activity of D1 receptor, and antagonize activity of D2 receptor in the meantime, such medicaments should have good prospects for the treatment of schizophrenia.
Parkinson's disease is a chronic progressive degenerative diseasea with brain dopaminergic neuron loss as main feature. For a long time, L-Dopamine is a “gold standard” for the treatment of Parkinson's disease. However, long-term administration of L-Dopamine is often accompanied by high incidence of treatment-related complications, such as dyskinesias, efficacy loss and “on-off” phenomenon and the like, which are named as “L-Dopamine long-term syndrome” and can not delay disease progression.
DA receptor agonist is one of various substitutive therapies for Parkinson's disease and mainly used with L-Dopamine in Parkinson patients having dyskinesia. DA receptor agonist is superior to L-Dopamine, the mechanism of which is that in the later stages of Parkinson's disease, dopamine decarboxylase activity of the nigrostriatal DA system is depleted, therefore, exogenous L-Dopamine can not be transformed into DA through decarboxylation, and at that time, even a large dose of L-Dopamine preparations is ineffective; however, the function of DA receptor agonist is irrelevant to DA synthesis and does not depend on the activity of dopa decarboxylase, the molecular conformation thereof is similar to that of DA, DA receptor agonist works by directly acting on striatal synaptic DA receptor, primarily D1 receptor, in part on D2 receptors; therefore, the combination of DA receptor agonist can further improve motor symptoms of Parkinson's disease. Based on such theory, if D1 receptor agonist with selectivity can be developed, it is possible to provide a class of medicaments with good effect for the treatment of Parkinson's disease. Currently, some companies have developed various D1 receptor selective agonists with selectivity, many of which have been studied in clinical trail, but many medicament candidates have low selectivity and obvious side effect. Therefore, the development of D1 receptor selective agonist with high selectivity and little side effect will undoubtedly have huge advantages for the treatment of Parkinson's disease.
The hexahydrodibenzo[a,g]quinolizine compounds are a class of alkaloids extracted from traditional Chinese medicine Corydalis Tuber and Stephania genus plants, which have a common chemical nucleus containing two-isoquinoline structure and having —OCH3 in C2, C3, C9, and C10 or substituted by —OH. Such alkaloids have various biological activities, including anti-inflammatory effect, antibacterial effect, anti-leukemia effect, anti-cancer effect and so on. Academician Jin GuoZhang, et al. have systematically studied the pharmacological effects of hexahydrodibenzo[a,g]quinolizine compounds and demonstrated that levorotatory tetrahydropalmatine has good analgesic effect accompanied by sedation, tranquillizing effect and hypnotic effect, while dextrorotatory tetrahydropalmatine has no significant analgesic effect. It is also demonstrated that the target of levorotatory tetrahydropalmatine or other hexahydrodibenzo[a,g]quinolizine alkaloids is dopamine receptor. Jin Guozhang has also reported for the first time that l-Stepholidine (l-SPD), one of hexahydrodibenzo[a,g]quinolizine compounds (THPBs), is a lead compound with the dual role of D1 agonist and D2 antagonistic activity (Jin G Z. TiPS, 2002, 23-24). l-SPD, in clinical trials, has shown good therapeutic effects on positive and negative symptoms and has non-classical stabilizer features, and can be likely developed into a new class of antipsychotic medicaments. Shen Jingshan, Yang Yushe et al. disclosed a preparation method and use of l-SPD derivatives and levorotatory Chloroscoulerine with antipsychotic effect, wherein Scoulerine methanesulfonate has good water solubility and stability (WO2008/014661, CN03151464, and CN1900076). However, the structures of these compounds are not greatly modified, most of the compounds have weak activity on D2 receptor, and many compounds have no 5-HT activity, poor solubility and low bioavailability. Meanwhile, these compounds showed a certain degree of selectivity in D1 receptor vs D2 receptor. Therefore, it is significant to continually modify hexahydrodibenzo[a,g]quinolizine compounds, especially to develop compounds with better D2 activity or develop D1 receptor agonists with better selectivity, thereby providing beneficial help for treating Parkinson's disease.
The present invention provides the synthesis and use of a class of hexahydro-dibenzo[a,g]quinoline compounds with novel structures. Some compounds with such structures show good selectivity in D1 vs D2 wherein many compounds also have 5-HT activity. Other compounds have dual pharmacological activities of good D1 agonist and D2 antagonist and good solubility, and can be used in the preparation of the medicaments for treating neurological diseases, especially dopamine receptors and serotonin receptor-associated neurological disease.